During the past five years, we have synthesized over 200 new nucleosides analogues. Biological evaluation by Dr. Raymond Schinazi of Emory University/VA Medical Center suggested that several targeted compounds had potent and selective anti-HIV-1 activities in human lymphocytes. From these efforts we have identified at least six promising compounds. These include 3'-azido-2',3'-dideoxyuridine (AzddU, AZDU or CS-87), 3'-azido- 2',3'-dideoxy-5-methylcytosine (AZMdC), N6-Me-ddA, N6-methyl-2'-F-ddA, 3'- deoxy-3'fluoro-5-methylcytosine, and 9-beta-(2,3-dideoxyribofuranosyl)-6- chloropurine (6-CI-P). Among these nucleosides, AZdU has been undergoing clinical trials in patients with AIDS and AIDS-related complex. In order to determine the usefulness of the other nucleosides, biochemical, pharmacological, and toxicological studies are in progress. We plan to continue exploring the structure-activity relationships of 3'- azido-2',3'-dideoxy-,2',3'-dideoxy-and 2',3'-didehydro-2',3'-dideoxy- nucleosides. Stereoselective synthetic methods developed in our laboratory will be used to facilitate the synthesis. Additionally, new classes of anti-HIV nucleosides, BCH-189 and dioxolane-T analogues and their C- nucleosides will be synthesized and evaluated as potential anti-HIV agents. Asymmetric synthesis of 1,3-dioxolane and 1,3-oxothiolane moieties have recently been accomplished by our group from a chiral template, D-mannose, which can be used for condensation with various heterocyclic moieties, resulting in enantiomerically pure nucleosides. Additionally, we also plan to synthesize oxetanocin analogs and three-membered carbocyclic ring nucleosides. If time permits, nucleosides with various substituted heteroatoms (sulfur, oxygen, nitrogen, and selenium) in the ribose ring will be synthesized to study the exhaustive structure-activity relationships of the carbohydrates and heterocyclic moieties. The long term goal of this application is to discover improved and new anti-HIV nucleosides that do not show cross-resistance with the existing anti-HIV nucleosides. Additionally, the proposed compounds will also be evaluated in other anti-viral screening systems including HCMV, herpes, RSV, human hepatitis B virus.